Recent work has demonstrated that the platelet Na/Ca exchanger (NCX) in human beings is identical to the retinal rod NCX. This exchanger plays an important role in regulating platelet Ca stores and it is driven not only by the Na electrochemical gradient but also by the K electrochemical gradient across the platelet plasma membrane. In addition, platelets express the alpha3 isoform of the Na-pump, an isoform with a heightened sensitivity to cardiac glycosides. These features of the platelet ion transport strongly link platelet Ca metabolism to fluctuations in systemic Na and K homeostasis and to the activity of the platelet Na-pump. At the core of this project is the hypothesis that the link between platelet Ca homeostasis and systemic Na/K regulation explains some cardiovascular effects of high Na and high K intakes that are independent of the effects of Na and K intakes on blood pressure. Three specific aims will explore this hypothesis. Specific Aim 1 will decipher the physiological and molecular characteristics of the Na-pump in human platelets, focusing on the alpha3 subunit isoform in these cells and its sensitivity to cardiac glycosides. The results will provide a better appreciation of the link between platelet NCX and the Na-pump. Specific Aim 2 will test the hypothesis that a high Na intake raises cytosolic Na, lowers cytosolic K, and inhibits the NCX to increase platelet Ca stores and platelet reactivity in human beings. Specific Aim 3 will test the hypothesis that a high K intake lowers cytosolic Na, raises cytosolic K and stimulates platelet NCX activity to diminish platelet Ca stores and platelet reactivity in human beings. Findings of this project might identify previously unknown cardiovascular effects of dietary Na and K, thereby revealing a new dimension of 'salt sensitivity' in human beings.